Novel process for the preparation of linezolid and related compounds

ABSTRACT

The present invention provides a novel process for preparation of 5-aminomethyl substituted oxazolidinones, key intermediates for oxazolidinone antibacterials including linezolid. Thus linezolid is prepared by a) reacting 3-fluoro-4-morpholinyl aniline with R-epichlorohydrin; b) subjecting N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline produced above to carbonylation; c) reacting (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone produced above with potassium phthalimide; d) reacting (S)—N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide produced above with hydrazine hydrate; and e) reacting S—N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine produced above with acetic anhydride to produce linezolid.

FIELD OF THE INVENTION

The present invention provides a novel process for preparation of5-aminomethyl substituted oxazolidinones, key intermediates foroxazolidinone antibacterials.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,688,792 (U.S. Pat. No. 5,688,792) disclosed oxazine andthiazine oxazolidinone derivatives. The compounds are antimicrobialagents. Among them linezolid, chemicallyN-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideis the most important antibacterial agent. Linezolid is represented bythe following structure:

Processes for preparation of linezolid were described in U.S. Pat. No.5,837,870, WO 99/24393, WO 95/07271, J.Med.Chem. 39(3), 673-679, 1996and Tetrahedron Lett., 40(26), 4855, 1999.

According to prior art processes, the 5-hydroxymethyl substitutedoxazolidinones are converted to the corresponding 5-aminomethylsubstituted oxazolidinones, key intermediates in the production ofoxazolidinone antibacterial pharmaceuticals.

The prior art processes for preparing 5-aminomethyl substitutedoxazolidinones are associated with many drawbacks. For instant in thepreparation of linezolid, WO 95/07271 uses butyl lithium at very lowtemperature (−78° C.) and WO 99/24393 uses phosgene gas. It is knownthat the handling of butyl lithium and phosgene gas are difficult andthe person skilled in the art appreciate a process that produces theproduct in good yield avoiding the ‘difficult to handle’ reagents.

We have discovered a novel process for preparation of 5-aminomethylsubstituted oxazolidinone key intermediates using novel intermediates.The novel process solve the drawbacks associated with the priorprocesses and so, commercially viable for preparing these and relatedcompounds.

SUMMARY OF INVENTION

The present invention provides a novel process to prepare 5-aminomethylsubstituted oxazolidinones of formula I:

wherein

X is O, S, SO or SO₂;

R₁ is H, CH₃ or CN;

R₂ is independently H, F or Cl;

R₃ is H or CH₃;

n is 0, 1 or 2;

which comprises;

-   a) reacting a compound of formula II:    wherein R₁, R₃, X, R₂ and n are as defined in formula I;-   with R-epichlorohydrin of formula III:

to produce a compound of formula IV:

wherein R₁, R₃, X, R₂ and n are as defined in formula I;

-   b) converting the product of step (a) to chloromethyl oxazolidinone    compound of formula V:

wherein R₁, R₃, X, R₂ and n are as defined in formula I; and

-   c) converting the chloromethyl oxazolidinone compound of step (b) to    aminomethyl oxazolidinone of formula I.

The compounds of formula IV are novel and provides another aspect of thepresent invention.

The compounds of the formula V with the exception of the compound offormula V wherein R₁═R₃ is H; one R₂ is H and the other R₂ is F; X is O;and n is 1 are novel.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel process for preparing5-aminomethyl substituted oxazolidinones of formula I:

wherein

X is O, S, SO or SO₂;

R₁ is H, CH₃ or CN;

R₂ is independently H, F or Cl;

R₃ is H or CH₃;

n is 0, 1 or 2.

-   Step—a) Phenyl amine compound of formula II:

wherein R₁, R₃, X, R₂ and n are as defined in formula I;

is reacted with R-epichlorohydrin of formula III:

to provide chlorohydrin compound of formula IV:

wherein R₁, R₃, X, R₂ and n are as defined in formula I.

The quantity of epichlorohydrin is not critical, but for better yield atleast one molar equivalent is required per equivalent of phenyl amine offormula II.

The reaction may be carried out with or without using a solvent.

If the reaction is carried out in the absence of solvent, the compoundsof formula II and the formula III are usually heated together forsufficient time to obtain the compound of formula IV. The reactants areheated preferably to about 40-150° C. and more preferably to about40-120° C. The time required for the conversion is 30 minutes to 10hours, preferably 2 to 6 hours.

Preferably, the reaction between the compounds of formula II and formulaIII is carried out in a solvent. Any solvent, which is neutral towardsthe reactants, may be used. Operable solvents include cyclic ethers suchas tetrahydrofuran; amides such as N,N-dimethylformamide andN,N-dimethylacetamide; acetonitrile; and alcohols such as methanol,ethanol, t-amyl alcohol, t-butyl alcohol and Isopropyl alcohol; and amixture thereof. Preferable solvent is selected from methanol, isopropylalcohol and N,N-dimethylformamide.

The reaction is performed at or below boiling temperature of the solventused, more preferably between 10° C. and boiling temperature of thesolvent used and even more preferably at boiling temperature of thesolvent used.

Time required for completion of the reaction depends on factors such assolvent used and temperature at which the reaction is carried.

The product obtained may be used directly in the next step, or it can beisolated from the reaction mixture and used in the next step.

The compounds of formula IV are novel and provides another aspect of thepresent invention.

-   Step—b) The chlorohydrin compound of formula IV produced as above is    subjected to carbonylation to provide chloromethyl oxazolidinone    compound of formula V:    wherein R₁, R₃, X, R₂ and n are as defined in formula I.

The carbonylation is performed using any carbonylating reagent commonlyknown for such purpose. Among them carbonyldiimidazole, phosgene, methylchloroformate, benzyl chloroformate and phenylchloroformate arepreferred; carbonyldiimidazole being more preferred.

The carbonylation reaction is preferably performed by contacting thechlorohydrin compound of formula IV with carbonylating agent in thepresence of an aprotic solvent or a mixture thereof. More preferably thechlorohydrin compound of formula IV is reacted with at least one molarequivalent of the carbonylating agent in the presence of an aproticsolvent such as methylene dichloride, ethylenedichloride or chloroform.

The compound of formula V wherein R₁═R₃ is H; X is O; one R₂ is H andthe other R₂ is F; n is 1((5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone)is mentioned in the J. Pharmaceutical and biomedical analysis, 2002, 30(3), 635-642 as an possible impurity in linezolid. We disclosed the useof this compound and related compounds in the preparation of thecompounds of formula I.

The compounds of formula V, wherein X, R₁, R₂, R₃ and n are as definedin formula I with the exception of the compound of formula V, whereinR₁═R₃ is H; one R₂ is H and the other R₂ is F; X is O; and n is 1 arenovel and provide another aspect of present invention.

-   Step—c) The chloromethyl oxazolidinone compound of formula V    produced as above is converted to aminomethyl oxazolidinone compound    of formula I.

Preferred 5-amino methyl substituted oxazolidinones are the compounds offormula I, wherein R₁═R₃ is H; R₂ is independently H and F; X is O or S;and n is 1. More preferred 5-amino methyl substituted oxazolidinones arethe compounds of formula I, wherein R₁═R₃ is H; R₂ is independently Hand F; X is O; and n is 1. Still more preferred 5-amino methylsubstituted oxazolidinones are the compounds of formula I, wherein R₁═R₃is H; one R₂ is H and the other R₂ is F; X is O; and n is 1.

The conversion of the compound of formula V to the compound of formula Ican be achieved by a method known for the conversion of aliphaticchloride to the corresponding amine.

Thus, for example, chlorine atom of the chloromethyl oxazolidinonecompound is first replaced by azide using azide source such as sodiumazide or potassium azide to provide azide compound of formula VI:

wherein R₁, R₃, X, R₂ and n are as defined in formula I.

The azide compound is known and can be converted to the aminomethyloxazolidinone compound by known methods such as those described in U.S.Pat. No. 5,688,792. For example, the azide compound is hydrogenatedusing for example palladium/carbon catalyst to provide the aminomethyloxazolidinone compound.

Alternatively, the chloromethyl oxazolidinone compound is reacted withpotassium phthalimide to provide phthalimido compound of formula VII:

wherein R₁, R₃, X, R₂ and n are as defined in formula I.

The reaction is carried out by contacting the 5-chloromethyloxazolidinones with potassium phthalimide in a solvent or mixture ofsolvents. Selection of solvent is not critical, but preferable solventsare those that dissolve both the chloromethyl oxazolidinones andpotassium phthalimide to ensure maximum contact between the reactantsresulting in faster reaction. However, the process is also operable withsolvents that only partially dissolve the chloromethyl oxazolidinones orpotassium phthalimide. The preferable solvent is dimethyl formamide oracetonitrile.

The reaction is performed preferably between about 10° C. and theboiling temperature of the solvent used, more preferably between 40° C.and 100° C. and most preferably at the boiling temperature of thesolvent used.

Time required for completion of the reaction depends on factors such assolvent used and temperature at which the reaction is carried out. Forexample, if the reaction is carried out by contacting the 5-chloromethyloxazolidinones with potassium phthalimide in dimethylformamide underreflux conditions, about 2 to 10 hours is required for the reactioncompletion.

The phthalimido compounds of formula are known and can be converted tothe aminomethyl oxazolidinone compounds by using for example Hydrazinehydrate or aqueous methylamine. These methods are known and aredescribed for example in U.S. Pat. No. 5,688,792.

The aminomethyl oxazolidinone compounds of formula I are acylated byknown methods using acylating agents such as acyl halides or acylanhydrides to form the corresponding 5-acylaminomethyloxazolidinonecompounds of formula VIII.

wherein R₁, R₃, X, R₂ and n are as defined in formula I; R represents C₁to C₈ straight or branched alkyl groups. The preferred alkyl group isCH₃.

The acylation can be carried out by known methods such as thosedescribed in U.S. Pat. No. 5,688,792.

One compound of formula VIII can be converted to another compound offormula VIII. Thus for example compounds of formula VIII, wherein X is Scan be converted to the compounds of formula VIII, wherein X is SO orSO₂ by the methods such as those disclosed in U.S. Pat. No. 5,688,792.

The 5-acyl amino methyl substituted oxazolidinone of formula VIII areknown to be antibacterial pharmaceutical agents.

R-Epichlorohydrin has the right configuration to obtain the compounds offormula I and VIII. The configuration of epichlorohydrine is retainedthrough out the sequence of reactions of the invention. However, it isreadily apparent to one skilled in the art that one could easily performthe identical process steps with the opposite enantiomeric form orracemic form to obtain the corresponding stereo isomers.

Therefore, using the chemistry of the claimed process with any of theenantiomeric forms is considered equivalent to the claimed processes.

In particular most important compound of formula VIII is linezolid(VIII, R₁ and R₃ is H; X is O, one R₂ is H and the other R₂ is F; n is1). The most preferred process for preparing linezolid is described asunder:

-   a) 3-fluoro-4-morpholinyl aniline (formula II, R₁═R₃ is H; X is O;    one R₂ is H and the other R₂ is F; and n is 1) is reacted with    R-epichlorohydrin (formula III) to produce    N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline    (formula IV, R₁═R₃ is H; X is O; one R₂ is H and the other R₂ is F;    and n is 1);

The quantity of epichlorohydrin is not critical, but for better yield atleast one molar equivalent is required per equivalent of3-fluoro-4-morpholinyl aniline.

Any solvent, which is neutral towards the reactants, may be used.Operable solvents include cyclic ethers such as tetrahydrofuran; amidessuch as N,N-dimethylformamide and N,N-dimethylacetamide; acetonitrile;and alcohols such as methanol, ethanol, t-amyl alcohol, t-butyl alcoholand Isopropyl alcohol. Preferable solvent is selected from methanol,isopropyl alcohol and N,N-dimethylformamide.

The reaction is performed at or below boiling temperature of the solventused, more preferably between 10° C. and boiling temperature of thesolvent used and even more preferably at boiling temperature of thesolvent used.

Time required for completion of the reaction depends on factors such assolvent used and temperature at which the reaction is carried. Forexample, if the reaction is carried out in isopropyl alcohol solvent atthe boiling temperature of the solvent, about 15 hours is required forthe reaction completion.

The product obtained can be used directly in the next step, or it can beisolated from the reaction mixture and used in the next step.

-   b) N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline    produced as above is subjected to carbonylation to provide    (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone    (Formula V, R₁═R₃ is H; X is O; one R₂ is H and the other R₂ is F;    and n is 1).

The carbonylation is performed using any carbonylating reagent commonlyknown for such purpose. Among them carbonyldiimidazole, phosgene, methylchloroformate, benzyl chloroformate and phenylchloroformate arepreferred; carbonyldiimidazole being more preferred.

The carbonylation reaction is preferably performed by contacting theN-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline withcarbonylating agent in the presence of an aprotic solvent or a mixtureof aprotic solvents. More preferably theN-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline isreacted with at least one molar equivalent of the carbonylating agent inthe presence of an aprotic solvent such as methylene dichloride,ethylenedichloride or chloroform.

-   c)    (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone    produced as above is reacted with potassium phthalimide to provide    (S)—N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide    (Formula VII, R₁═R₃ is H; X is O; one R₂ is H and the other R₂ is F;    and n is 1);

The reaction is carried out by contacting the(5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinonewith potassium phthalimide in a solvent or a mixture of solvents.Selection of solvent is not critical, but preferable solvents are thosethat dissolve both the chloromethyl oxazolidinones and potassiumphthalimide to ensure maximum contact between the reactants resulting infaster reaction. However, the process is also operable with solventsthat only partially dissolve the chloromethyl oxazolidinones orpotassium phthalimide. The preferable solvent is dimethyl formamide oracetonitrile.

The reaction is performed preferably between about 10° C. and theboiling temperature of the solvent used, more preferably between 40° C.and 100° C. and most preferably at the boiling temperature of thesolvent used.

Time required for completion of the reaction depends on factors such assolvent used and temperature at which the reaction is carried out. Forexample, if the reaction is carried out by contacting the 5-chloromethyloxazolidinones with potassium phthalimide in dimethylformamide underreflux conditions, about 3 to 7 hours is required for the reactioncompletion.

-   d)    (S)—N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide    produced as above is reacted with hydrazine hydrate or aqueous    methyl amine to produce    S—N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine    (Formula I, R₁═R₃ is H; X is O; one R₂ is H and the other R₂ is F;    and n is 1). These methods of deprotection are known and described    for example in U.S. Pat. No. 5,688,792.-   e)    S—N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine    is reacted with acetic anhydride to produce linezolid.

The following examples are given for the purpose of illustrating thepresent invention and should not be considered as limitations on thescope and spirit of the invention.

EXAMPLES Example 1

3-Fluoro-4-morpholinyl aniline (39 g) is mixed with R-epichlorohydrin(18.5 g), isopropyl alcohol (200 ml) is added and heated for 16 hours atreflux temperature. The solvent is distilled to give 57 gm ofN-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline.

Example 2

N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline (57 g)is dissolved in methylene dichloride (600 ml), diimidazolyl carbonyl (32g) is added at ambient temperature and the reaction mixture is stirredfor 20 hours. Then washed with water and distilled methylene dichlorideto give 48 gm of(5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone.

Example 3

The mixture of(5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone(60 g), potassium phthalimide (40 g) and Dimethyl formamide (400 ml) isheated for 5 hours at reflux temperature. The reaction mixture is cooledto ambient temperature, poured in to 2 L water and filtered the solid togive 50 gm(S)—N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide.

Example 4

Methanol (240 ml) and Hydrazine hydrate (26 g) are added to a flaskcontaining the(S)—N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide(40 g), heated for 1 hour at reflux temperature and cooled to roomtemperature. Then water (500 ml) is added to the reaction mass andextracted with methylene dichloride (300 ml). The combined extractionswere washed with water (100 ml) and the solvent distilled to give 20 gmofS—N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine.

Example 5

S—N-[[3-[3-Fluoro4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine(20 gm) is dissolved in Ethyl acetate (200 ml), Acetic anhydride (20 gm)is added drop wise at ambient temperature and stirred for 1 hour. Thereaction mixture is then cooled to 0-5° C., filtered the solid andre-crystallized from Isopropyl alcohol (400 ml) to give 16 gm ofN-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.

1-51. (canceled)
 52. A compound of formula IV:

wherein X is O, S, SO or SO₂; R₁ is H, CH₃or CN; R₂ is independently H,F or Cl; R₃ is H or CH₃; n is 0, 1 or
 2. 53. The compound of formula IVas defined in claim 52, wherein R₁═R₃ is H; R₂ is independently H and F;X is O or S; and n is
 1. 54. The compound of formula IV as defined inclaim 53, wherein R₁═R₃is H; one R₂is H and the other R₂is F; X is O;and n is
 1. 55-58. (canceled)